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GAN: Mutations in the Gigaxonin Gene

Paper Type: Free Essay Subject: Biology
Wordcount: 2949 words Published: 8th Feb 2020

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GAN: Mutations in the Gigaxonin Gene


Giant Axonal Neuropathy (GAN), is a disorder that effects the loss of movement and sensation. GAN is an inherited neurological disorder that is named and characterized by the axons that present outside the normal range. The uniquely large, consequently named giant axons, are incapable of communicating properly with the bodies nervous system which results in a decreased neurological response, primarily effecting the peripheral nervous system. Since the peripheral nervous system provides the body with motor function, persons with giant axonal neuropathy display difficulty in walking, motor coordination, and strength. As the disease later progresses to the central nervous system, the axons display continued deterioration which further impede mental function. The disease, although inheritable has shown to be autosomal recessive, which indicates that both parents would be carriers of the gene, however do not generally present with symptoms of the GAN disorder. The child instead receives from each parent one side of the mutated gigaxonin gene, and is thereby born with the giant axonal neuropathy.

Figure 1. Autosomal Recessive (http://www.hannahshopefund.org/about-gan/)

Further information will be provided on the etiology, diagnosis, and treatment of GAN as we examine the specific abnormality of the giant axons and their overall effect on the body.


Giant Axonal Neuropathy (GAN), per the U.S. National Library of Medicine has been linked to forty-seven different mutation of the GAN gene. The GAN gene is responsible for constructing the protein gigaxonin. Gigaxonin is important in helping the body rid itself of damaged or excessive numbers of organelles and proteins to ensure the room needed for the creation of healthy filaments.

Figure 2. Giant Axonal Neuropathy (https://ghr.nlm.nih.gov/condition/giant-axonal-neuropathy)

These healthy intermediate filaments provide foundation and strength to the body and allow for proper communication from the nervous system. “In nerve cells (neurons), gigaxonin is thought to help break down specialized intermediate filaments called neurofilaments. Neurofilaments comprise the structural framework that establishes the size and shape of nerve cell extensions called axons, which are essential for transmission of nerve impulses” (ghr.nlm.nih.gov/gene/GAN#conditions, 2016). As the giaxonin protein fails it allows the neurofilaments to instead become too heavily arranged in the giant axons. The failure of functionality of the giaxonin protein to prevent the gathering of these additional filaments results in the failure of the nervous system to have properly functioning nerve function. The nerve abnormalities result in a deterioration of normal motor function which eventually leads to fatal results with most not surviving past their twenties.


Clinical Symptoms:

Giant axonal neuropathy (GAN) is a fatal neurodegenerative disorder. It presents as an early-onset disorder with systems being reflected in the peripheral nerves. These peripheral nerves are responsible for carrying signals between the brain and spinal cord within the central nervous system. Although GAN is present at birth, symptoms are not conceptualized by the patient, and not necessarily visible to medical professionals until the infant begins missing neuropathy linked milestones. Albeit, per The National Institute of Health, the patient would be experiencing a lack of motor control, notable weakness in body strength, lack of sensation such as touch, pain, heat, along with diminished vision and hearing (ghr.nlm.nih.gov/condition/giant-axonal-neuropathy, 2016). Symptoms can be difficult to determine anytime a disorder is present at birth as there is no understanding of expected homeostasis or comparison to be made by the patient.

Clinical Signs:

During physical examinations and parental monitoring the impact of the central nervous system impairment due to giant axonal neuropathy within the infant would be noticeable and would continue to worsen over time. The first physical indication is often recognized with problems walking and coordinating movements; Wheelchair assistance will later be required. A physical characteristic of giant axonal neuropathy, involves the hair. The hair is often described as abnormally kinky, this distinctive indication appears in most GAN cases.

Figure 3. Example of Kinky Hair (http://blogs.plos.org/dnascience/2015/02/19/gan-gene-therapy-trial-gets-green-light/)

The National Organization of Rare Diseases notes the following list of other known indications, “intellectual disability, seizures, cerebellar signs, and pyramidal tract signs… most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade” (rarediseases.org/rare-diseases/giant-axonal-neuropathy/). GAN also impacts the autonomic nervous system, which can provide further indications such as bladder inconstance, constipation, as well as the improper functionality of the sweat glands.

Lab Test & Findings:

The structural makeup of the giant axons when reviewed under microscopic evaluation show missing mitochondria and other variations. Immunodiagnostic testing is used to look for variations in the quantities of gigaxonin. The National Center for Biotechnology Information (NCBI) notes 32 different genic test, ranging from numerous sequencing panels to hereditary neuropathy panels, and neuromuscular disorder panels. Molecular gene testing can focus on single gene or multi-gene panels. NCBI also notes “some multigene panels may include genes not associated…thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype” (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). Carrier testing is also indicated for siblings and family members, including prenatal testing. At earlier points nerve biopsy was indicated, however, this is no longer a followed practice.

Imaging Test & Studies:

Imaging test and functional studies can be helpful in identifying GAN. Electroencephalogram (EEG) detects electrical activity in your brain. Nerve conduction velocity(NCV) studies, which can track the response time of the nervous system to certain stimuli aid in understanding the patients response time versus a clinical norm. The brain magnetic resonance imaging (MRI) can also be helpful in the diagnosis of giant axonal neuropathy (GAN). The MRI is when “ the body is exposed to high-energy magnetic field…results in a two- or three- dimensional blueprint of cellular chemistry”(Tortora & Derrickson, 2017; p.23) allows physicians a more in depth representation of the central nervous system. White matter abnormalities tend to be visible on the brain MRI, as well as the cerebellar white matter (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). Magnetic resonance spectroscopy (MRS) is also indicated which adds to the MRI with a series of additional test that measure chemical composition.

Figure 4. MRI Image, A mild case of giant axonal neuropathy without central nervous system manifestation. (www.brainanddevelopment.com)

Differential Diagnosis

In some instances other disease show similar characteristics as giant axonal neuropathy (GAN). The National Library of Medicine cites the following hereditary neurological disorders: Menkes, a disorder associated to copper transport, presents with similar kinky hair structure and missed milestones during infancy, although they appear healthy until the age of 2-3 months, and then unlike GAN mortality happens generally around the age of 3 rather than in later stages of life. ARSA deficiency, metachromatic leukodystrophy, MLD which is associated to a breakdown of sulfides has onset during infancy, juvenile, and adult ranges (not confused with GAN due to age of onset) and presents with the similarity of weakness, slurred speech, seizures and other decreases in motor function. INAD or Seitelberger disease presents with the neurologic symptoms and effects the axons, but excludes the hair abnormalities. “In the past the term Dejerine-Sottas syndrome was used to designate severe childhood-onset genetic neuropathies of any inheritance; the term is no longer in general use” (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). In some instances inhalable toxins can also cause similar signs to occur, but will not present with hair similarities, and will present after exposure to the toxin.


Giant axonal neuropathy (GAN) treatment is primarily supportive in nature. This includes work with different therapist whom concentrate on speech and language deficiencies to improve the communicative aspects that are impacted by the disease. Other services include those who concentrate on mobility, such as physiotherapists who help to restore movement and function. This also includes work with support and mobility devices, such as walking aids and wheelchairs. Optometrist advise on the areas affecting the patients vision to include prescribing eyeglasses to assist with the quality of life. Pediatric neurologist also work with the patient to monitor the diseases progression and influences on the nervous system. Surgical involvement can be indicated in certain instances. (rarediseases.org/rare-diseases/giant-axonal-neuropathy/). In some cases orthopedic surgeons may be required to address the musculoskeletal system deformities, including foot deformities. Proper monitoring for the prevention of decubitus ulcers is also indicated.. Any number of minor surgical procedures are often performed to assist in this supportive nature, such as vision correction, nutritional support, and other required interventions. Genetic counseling, although not indicated for the patient as there has not been a reported case of reproduction of a GAN patient, is generally indicated for the family members due to the hereditary and recessive nature of the mutations in the gigaxonin gene (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). Numerous sources indicate a variety of clinical trials which can be found at www.clinicaltrials.gov, including that of human gene therapy by Mussche and colleagues (https://www.liebertpub.com). There are also supportive organizations available for the patients and families of those diagnosed with neurological disorders.


It is important to note GAN is not a curable disorder by rehabilitation, surgery or medications and the involvement of these medical professionals are there to improve the quality of life of the patient. “Individuals present with a motor and sensory peripheral neuropathy that may also involve the cranial nerves, resulting in facial weakness, optic atrophy, and ophthalmoplegia. Tendon reflexes are often absent” (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). Individuals suffering from GAN inevitably become wheelchair dependent within approximately ten years or sooner of diagnosis. More severe indications of neurological and muscular deformities lead to further immobility as the patient ages. Dementia is also noted as the disorder progresses. National Center for Biotechnology Information(NCBI) reports that death later results from secondary complications, such as respiratory failure as the patient reaches the age of 20-30. (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014).

Ethical Implications

As giant axonal neuropathy (GAN) is a genetic disorder that is identifiable via genetic testing the decision to not reproduce is an option that could be decided between two individuals who carry the recessive gene. This topic could present based on familial structures of recessive gene carriers or their own prior child who has been diagnosed with GAN. NCBI reports that “at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier… an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3” (www.ncbi.nlm.nih.gov/books/NBK1136/, 2014). These are significant odds of furthering the disorder with additional siblings, and future generations. For some religions preventing the birth of children is not supported within the belief structure. Other personal, cultural, or ethical issues that individuals may face could be in the decision to terminate a pregnancy following prenatal genetic testing. It would be important that a family work with the appropriate support systems and medical professionals while determining the appropriate actions for their individual circumstances.


Mutations in the gigaxonin gene are impactful to multiple body systems to include the nervous system and muscular system. The abnormally large axons, termed giant, results in a disorder that effects the loss of movement and sensation, to the degree of eventual premature death. Mobility and overall motor function is the primary indication of the disorder that will result in certain wheelchair assisted movement. Other areas of disfunction are neurological deficiencies such as slow mental development including dementia, as well as the impact on vision and hearing. Giant axonal neuropathy is not necessarily an immediately recognizable disorder, and does allow an individual to live with assistance for approximately 20-30 years. This is a significant life span with an inclusiveness of some level of quality of life considering some of the other more immediate and profound genetic disorders. With the continued efforts of doctors such as Silke Mussche, Bart Devreese, et. all in human gene therapy along with the continued efforts in stem cell research one could hope for continued progress in search for preventative care, responsive treatment, and ultimately a way to reverse the mutated genes.


  • “GAN Gene – Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, Aug. 2016, ghr.nlm.nih.gov/gene/GAN#conditions.
  • “Giant Axonal Neuropathy – Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, Sept. 2016, ghr.nlm.nih.gov/condition/giant-axonal-neuropathy.
  • “Giant Axonal Neuropathy.” NORD (National Organization for Rare Disorders), rarediseases.org/rare-diseases/giant-axonal-neuropathy/.
  • Kuhlenbäumer, Gregor, Timmerman, Vincent, et. all. “Giant Axonal Neuropathy.” Advances in Pediatrics., U.S. National Library of Medicine, 9 Oct. 2014, www.ncbi.nlm.nih.gov/books/NBK1136/.
  • Tortora, Gerard J., and Bryan Derrickson. Principles of Anatomy & Physiology. 15th ed., Wiley, 2017.
  • “Restoration of Cytoskeleton Homeostasis After Gigaxonin Gene Transfer for Giant Axonal Neuropathy.” A Definition for Wildness | Ecopsychology, www.liebertpub.com/doi/abs/10.1089/hum.2012.107.


  • Figure 1. “GAN Gene Therapy Trial Gets Green Light | DNA Science Blog.” Speakeasy Science, 19 Feb. 2015, blogs.plos.org/dnascience/2015/02/19/gan-gene-therapy-trial-gets-green-light/.
  • Figure 2. “Giant Axonal Neuropathy – Genetics Home Reference.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/giant-axonal-neuropathy.
  • Figure 3. “About GAN.” Hannah’s Hope Fund, www.hannahshopefund.org/about-gan/.
  • Figure 4. “A Mild Case of Giant Axonal Neuropathy without Central Nervous System Manifestation.” Journal – Elsevier, Mar. 2016, www.brainanddevelopment.com/action/showFullTextImages?pii=S0387-7604(15)00180


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